Combination antiretroviral therapy has become the standard of care for patients with human immunodeficiency virus (HIV) infection in the United States. Unfortunately, emergence of drug resistance hampers the long-term success of anti-retroviral treatment regimens. HI-443 is a rationally designed novel anti-HIV compound with potent activity against NNRTI-resistant HIV- 1. (US Patent Serial Number: 6,124,324). The primary goal of our ongoing research is to establish effective methods aimed at improving its oral bioavailability and develop a clinically applicable solid dosage formulation of HI-443. Recently, we developed 3 candidate formulations of HI-443 with good oral bioavailability. We are now proposing studies aimed at evaluating the toxicity profile of these 3 formulations in mice and examining their anti-HIV activity in a SCID mouse model of human AIDS. Under SPECIFIC AIM 1, we will study the toxicity profile of HI-443-F1, HI-443-F2, and HI-443-F3 in mice. We hypothesize that none of the 3 formulations of HI-443 will cause acute, subacute, or chronic toxicity at the proposed dose levels. Under SPECIFIC AIM 2, we will study the in vivo anti-HIV activity of HI-443-F1, HI-443-F2, and HI-443-F3 in a S C D mouse model of human AIDS. We hypothesize that HI-443-F3 will exhibit potent anti-HIV activity in Hu-PBL-SCID mice at nontoxic dose levels. After completion of this Phase I project, we will propose additional preclinical toxicity, pharmacokinetics, and efficacy studies in a Phase II application. The successful accomplishment of the goals may provide the basis for a new treatment strategy for multidrug resistant HIV-1.